Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a rare form of hemolytic anemia provoked by exposure to cold temperatures. When exposed to low enough temperatures, cold agglutinin antibodies demonstrate an increased affinity for carbohydrate antigens present on red blood cells (RBCs), leading to extravascular hemolysis. Cold agglutinins can arise in the setting of an underlying disease, such as infection or malignancy, but may also be present in otherwise healthy individuals without a predisposing condition.1

Spectrum of Disease

The severity of clinical manifestations in CAD can vary depending on the specific type of cold-sensitive antibodies involved. While cold agglutinin and Donath-Landsteiner antibodies recognize antigens on RBCs at low temperatures and result in extravascular hemolysis and anemia, cryoglobulin antibodies form immune complexes that have been implicated in systemic inflammatory syndrome, vasculitis, and an increased risk of venous thromboembolism (VTE).1

Individuals with circulating cold agglutinins may be largely asymptomatic until they have been exposed to temperatures cold enough to enhance antibody binding to RBCs.  Disease severity can range from mild symptoms, such as painful fingers and toes due to cold agglutinin-mediated acrocyanosis, up to catastrophic hemolysis and end organ failure in extreme cases.2 More commonly, anemia is present to some degree in most individuals, resulting in varying degrees of fatigue, weakness, and shortness of breath.  

Cutaneous Signs in CAD

Acrocyanosis is a common finding in individuals with CAD and is characterized by painful purple and gray discoloration of the extremities, fingers, nose, ears, and toes. Acrocyanosis is typically brought on by exposure to cold temperatures and resolves upon warming.3

Acrocyanosis is believed to be a vasospastic reaction resulting in chronic vasospasm of small cutaneous arteries and arterioles with subsequent compensatory dilation of capillary and postcapillary venules, causing cyanosis and sweating.4

Livedo reticularis is another cutaneous finding in patients with CAD. Caused by vasospasm, livedo reticularis manifests on the skin of the proximal extremities with a characteristic blanchable and reticulated pattern.5

Raynaud’s phenomenon may also be present in individuals with CAD and is differentiated from acrocyanosis by sharply demarcated borders and occasional triphasic color changes of the skin on the fingers and toes.6 Severe cases of Raynaud’s phenomenon leading to venospasm and tissue necrosis have been documented in individuals with CAD.7

Hemolytic Anemia

When exposed to cold temperatures, cold agglutinins bind to RBCs and cause agglutination and extravascular hemolysis, resulting in RBC destruction and anemia. The degree of anemia can range from mild, compensated hemolysis without significant anemia to severe, life-threatening anemia requiring blood products.8

Individuals with anemia secondary to CAD may experience typical symptoms of anemia, including fatigue, pallor, exertional shortness of breath, and dizziness. More severe cases of anemia can predispose patients to hemodynamic instability, confusion, and syncope.9

Hemoglobin levels can vary in patients with anemia secondary to CAD. Case series have demonstrated median hemoglobin levels of 9 to 10 g/dL, with some severely affected individuals exhibiting hemoglobin levels as low as 4.5 g/dL.10

Anemia due to hemolysis may be transient in some individuals, occurring only when there is an exposure to cold temperatures and resolving once temperatures increase. Case reports of individuals with CAD who live in northern climates and suffer from seasonal flares of hemolytic anemia have been documented.11

Hemolysis may also be exacerbated when cold agglutinins develop in the setting of an underlying illness, such as infection, malignancy, or trauma. This exacerbation of hemolysis in affected individuals with underlying CAD is differentiated from secondary cold agglutinin syndrome (CAS), which refers to cold agglutinins that arise solely due to a systemic stressor.12

Extravascular hemolysis can also lead to elevated levels of bilirubin, which may manifest with hemoglobinuria, jaundice, and splenomegaly.13

Venous Thromboembolism

Thrombotic events are a well-documented complication in individuals suffering from autoimmune diseases. The risk of VTE in individuals with CAD, however, is less clear and remains an area of continued research.

Notably, a Danish study of 72 patients with CAD demonstrated an increased risk of VTE when compared to matched controls (720 patients); however, the difference was not statistically significant. Subgroup analysis of individuals with severe hemolysis in CAD, on the other hand, did show a significantly increased risk of developing venous thrombosis.14  

A retrospective study reviewed insurance reports over a 10-year period and found a higher proportion of individuals experiencing venous, arterial, and cerebral thrombotic events in patients with CAD compared to matched controls.15

Venous thromboembolism due to CAD or other causes typically presents with unilateral leg or arm swelling, pain, overlying skin color and temperature changes, and distended superficial veins. Venous thromboembolism in the extremities can travel to the lungs, resulting in pulmonary embolism–a life threatening entity that often causes sharp chest pain with coughing or movement, shortness of breath, light-headedness, and hemodynamic instability.16


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  8. Aljubran SA. Cold agglutinin disease. Medscape. Updated August 23, 2021. Accessed September 28, 2021.
  9. Cold agglutinin disease. National Organization for Rare Disorders. Accessed September 28, 2021.
  10. Berensten S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. doi:10.1182/blood.2020005674
  11. Lyckholm LJ, Edmond MB. Images in clinical medicine: seasonal hemolysis due to cold-agglutinin syndrome. N Engl J Med. 1996;334(7):437. doi:10.1056/NEJM199602153340705
  12. Ulvestad E, Berentsen S, Mollnes TE. Acute phase haemolysis in chronic cold agglutinin disease. Scand J Immunol. 2001;54(1-2):239-242. doi:10.1046/j.1365-3083.2001.00960.x
  13. Cunha JP. Cold agglutinin disease signs, symptoms, causes, tests, and natural treatment. MedicineNet. Accessed September 28, 2021.
  14. Bylsma L, Gulbech Ording A, Rosenthal A, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi:10.1182/bloodadvances.2019000476
  15. Broome CM, Cunningham JM, Mullins M, et al. Increased risk of thrombotic events in cold agglutinin disease: a 10-year retrospective analysis. Res Pract Thromb Haemost. 2020;4(4):628-635. doi:10.1002/rth2.12333
  16. Deep vein thrombosis. Cleveland Clinic. Accessed September 28, 2021.

Reviewed by Debjyoti Talukdar, MD, on 9/28/2021.